The present invention relates to a novel acetylcholinesterase inhibitor.
Usefulness of an acetylcholinesterase inhibitor as an agent for treating and improving senile dementia such as Alzheimer type senile dementia, or cerebrovascular dementia, attention deficit hyperactivity disorder etc. came to be clinically highly regarded. In particular, donepezil hydrochloride (1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpiperidine hydrochloride) found with efforts of the present inventors is the only acetylcholinesterase inhibitor at present which can be sufficiently useful in respect of pharmacological activity, side effects, administration frequency, administration form etc., and fulfilling hopes of many patients and their families in nursing and clinical fields. In addition to donepezil hydrochloride, there are known acetylcholinesterase inhibitors such as rivastigmine (3-[1-(dimethylamino)ethyl]phenyl N-ethyl-N-methylcarbamate), metrifonate (dimethyl 2,2,2-trichloro-1-hydroxyethyl)phosphate), tacrine hydrochloride (1,2,3,4-tetrahydro-9-acridinamine), galanthamine hydrobromide, neostigmine, physostigmine etc. On one hand, there are some reports on processes for producing donepezil derivatives including donepezil hydrochloride, and for example JP-A 8-225527 and JP-A 11-263774 disclose a process for producing benzylpiperidylmethyl indanones, characterized by hydrogenating pyridinium salts with hydrogen in the presence of a hydrogenating catalyst.
It has been desired to provide highly useful acetylcholinesterase inhibitors in addition to donepezil hydrochloride.
In view of the circumstances described above, the present inventors made extensive study through which they found that both a compound represented by the formula: 
(wherein the xe2x80x9caxe2x80x9d moieties are the same as or different from each other and each represents a hydrogen atom or a C1-6 alkoxy group; n is an integer from 1 to 4; and Xxe2x80x2(xe2x88x92) represents a halide ion) and a compound represented by the formula: 
(wherein b, c, d and e are the same as or different from each other and each represents a hydrogen or a linear or branched C1-6 alkyl, C1-6alkoxy, C1-6alkoxy carbonyl, C1-6alkyl aminocarbonyloxy, di (C1-6alkyl)-aminocarbonyloxy or a halogen; and Xxe2x80x3(xe2x88x92) represents an anion in the series of chloride, bromide, iodide and sulfate) exhibit an excellent inhibitory action on acetylcholinesterase. Further, on the basis of these findings, they found that a 1-benzylpyridinium salt represented by the formula: 
(wherein R1, R2, R3 and R4 are the same or different, and represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6alkoxy carbonyl group, a C1-6 alkyl aminocarbonyloxy group or a di (C1-6 alkyl)-aminocarbonyloxy group; R5 represents a hydrogen atom, a halogen atom, a C1-6alkyl group, a C2-6 alkenyl group or a C2-6 alkynyl group; the partial structure: 
is a group represented by the formula  greater than C(R6)xe2x80x94CH2xe2x80x94 (wherein R6 is a hydrogen atom or a halogen atom) or  greater than Cxe2x95x90CHxe2x80x94; Xxe2x88x92 represents a halide ion or organic sulfonic acid ion; and m is 0 or an integer from 1 to 5) exhibits an excellent inhibitory action on acetylcholinesterase, and accomplished the present invention.
That is, the first aspect according to the present invention is (1) an acetylcholinesterase inhibitor comprising a 1-benzylpyridinium salt represented by the above formula (I). Further, (2) in the above item (1), R1, R2, R3 and R4 may be the same as or different from each other and each represents a hydrogen atom or a C1-6 alkoxy group; (3) in the above item (1), R1, R2 R3 and R4 may be the same as or different from each other and each represents a hydrogen atom or a methoxy group; (4) in the above item (1) , R1 and R4 may represent a hydrogen atom; and R2 and R3 may represent a methoxy group; (5) in the above item (1), R5 may be a hydrogen atom; (6) in the above item (1), the partial structure: 
may be a group represented by the formula  greater than C (R6) xe2x80x94CH2xe2x80x94 (wherein R6 is a hydrogen atom or a halogen atom) ; (7) in the above item (1), m may be 0, 2 or 4; (8) in the above item (1), the halide ion represented by Xxe2x88x92 maybe a chloride ion, bromide ion or iodide ion, preferably a chloride ion or bromide ion; (9) in the above item (1), the organic sulfonic acid ion represented by Xxe2x88x92 may be a methanesulfonate ion, trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion or camphor sulfonate ion; (10) in the above item (1), the 1-benzylpyridinium salt may be a compound represented by the formula: 
wherein R1, R2, R3, R4 and Xxe2x88x92 have the same meanings as defined above; and n is an integer from 1 to 6; (11) in the above item (1), the 1-benzylpyridinium salt may be a compound represented by the formula: 
wherein R1, R2, R3, R4 and Xxe2x88x92 have the same meanings as defined above; and p is 0 or an integer from 1 to 5; (12) in the above item (1), the preparation may be an agent for treating, preventing or improving senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder; and (13) in the above item (12), the senile dementia may be Alzheimer type senile dementia.
The second aspect according to the present invention is (14) a pharmaceutical preparation comprising a 1-benzylpyridinium salt represented by the formula: 
wherein R1, R2, R3, R4, R5, the partial structure: 
Xxe2x88x92 and m have the same meanings as defined above. Further, the third aspect according to the present invention is (15) use of a 1-benzylpyridinium salt represented by the formula: 
(wherein R1, R2, R3, R4, R5, the partial structure: 
Xxe2x88x92 and m have the same meanings as defined above) for producing an acetylcholinesterase inhibitor.
The present invention provides a method of preventing, treating or improving a disease against which an inhibitory action on acetylcholinesterase is efficacious for prevention, treatment or improvement, by administering a pharmacologically effective dose of the 1-benzylpyridinium salt represented by the above formula (I) to a patient.
In the present invention, the disease against which an inhibitory action on acetylcholinesterase is efficacious for prevention, treatment or improvement includes senile dementia such as Alzheimer type senile dementia, and cerebrovascular dementia and attention deficit hyperactivity disorder.
Hereinafter, the meanings of symbols, terms etc. used in the specification are described, and the present invention is described in detail.
In the specification, the structural formulae of the compound may, for convenience"" sake, indicate a certain isomer, but the present invention encompasses all possible isomers which can occur in the structures of the compound, for example geometric isomer, optical isomer based on asymmetrical carbon, stereoisomer and tautomer, and a mixture of such isomers, so the compound according to the present invention may be any isomers or a mixture thereof without limitation to the formulae shown for convenience"" sake. Accordingly, the compound according to the present invention can have an intramolecular asymmetrical carbon, thus occurring as optically active isomers or racemic modifications, and any of such compounds are included in the present invention without limitation. When there is crystal polymorphism, the compound according to the present invention may be in a single crystal form or a mixed crystal form without limitation. Compound (I) or salts thereof may be anhydrides or hydrates, any of which fall under the claims in the specification. Further, metabolites formed by decomposition of Compound (I) in vivo, and prodrugs of Compound (I) or salts thereof, also fall under the claims in the specification.
The xe2x80x9chalogen atomxe2x80x9d used in the specification refers to an atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.
The xe2x80x9cC1-6 alkyl groupxe2x80x9d represented by R1, R2, R3 and R4 in the specification refers to an alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group etc., preferably a methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group and tert-butyl group.
The xe2x80x9cC1-6 alkoxy groupxe2x80x9d represented by R1, R2, R3 and R4 in the specification refers to an alkoxy group having 1 to 6 carbon atoms, and examples thereof include a methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group, 2,3-dimethylbutyloxy group, 1,3-dimethylbutyloxy group, 2-ethylbutoxy group, 1,3-dimethylbutoxy group, 2-methylpentoxy group, 3-methylpentoxy group, hexyloxy group etc., preferably a methoxy group, ethoxy group, n-propoxy group and iso-propoxy group.
The xe2x80x9cC1-6 alkoxycarbonyl groupxe2x80x9d represented by R1, R2, R3 and R4 in the specification refers to a group in which a C1-6 alkoxy group having the same meaning as defined above bound to a carbonyl group. For example, a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, iso-propoxycarbonyl group, n-butoxycarbonyl group, iso-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, hexyloxycarbonyl group etc., preferably a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group and iso-propoxycarbonyl group.
The xe2x80x9cC1-6alkyl aminocarbonyloxy groupxe2x80x9d represented by R1, R2, R3 and R4 in the specification refers to an aminocarbonyloxy group whose nitrogen atom has been substituted with a C1-6alkyl group having the same meaning as defined above, and examples thereof include a methylaminocarbonyloxy group, ethylaminocarbonyloxy group, n-propylaminocarbonyloxy group, iso-propylaminocarbonyloxy group, n-butylaminocarbonyloxy group, iso-butylaminocarbonyloxy group, tert-butylaminocarbonyloxy group, n-pentylaminocarbonyloxy group, iso-pentylaminocarbonyloxy group, neopentylaminocarbonyloxy group, hexylaminocarbonyloxy group, 1-methylpropylaminocarbonyloxy group, 1-methyl butyl aminocarbonyloxy group, 2-methylbutylaminocarbonyloxy group etc.
The xe2x80x9cdi (C1-6 alkyl)-aminocarbonyloxy groupxe2x80x9d represented by R1, R2, R3 and R4 in the specification refers to an aminocarbonyloxy group whose nitrogen atom has been substituted with two C1-6 alkyl groups, and examples thereof include a dimethylaminocarbonyloxy group, diethylaminocarbonyloxy group, di(n-propyl)-aminocarbonyloxy group, di-(iso-propyl)-aminocarbonyloxy group, di(n-butyl)-aminocarbonyloxy group, di(iso-butyl)-aminocarbonyloxy group, di-(tert-butyl)-aminocarbonyloxy group, di(n-pentyl)-aminocarbonyloxy group, di-(iso-pentyl)-aminocarbonyloxy group, di-(neopentyl)-aminocarbonyloxy group, di-(n-hexyl)-aminocarbonyloxy group, di-(1-methylpropyl)-aminocarbonyloxy group, di-(1-methylbutyl)-aminocarbonyloxy group, di-(2-methylbutyl)-aminocarbonyloxy group etc.
As the preferable mode of R1, R2, R3 and R4 in the specification, R1, R2, R3 and R4 are the same as or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group, a C1-6alkyl group or a C1-6 alkoxy group; more preferably, they are the same as or different from each other and each represents a hydrogen atom, a halogen atom, a hydroxyl group, a nitrile group or a C1-6alkoxy group; further preferably, they are the same as or different from each other and each represents a hydrogen atom or a C1-6alkoxy group; and the most preferably, R1 and R4 represent a hydrogen atom while R2 and R3 are the same as or different from each other and each represents a C1-6 alkoxy group (for example, a methoxy group, ethoxy group etc.).
The xe2x80x9chalogen atomxe2x80x9d and xe2x80x9cC1-6 alkyl groupxe2x80x9d represented by R5 in the specification refer to a halogen atom and C1-6alkyl group each having the same meaning as defined above.
The xe2x80x9cC2-6 alkenyl groupxe2x80x9d represented by R5 in the specification refers to an alkenyl group having 2 to 6 carbon atoms, and examples thereof include linear or branched C2-6 alkenyl groups such as a vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 2-buten-1-yl group and 2-buten-2-yl group, preferably a vinyl group, allyl group and isopropenyl group.
The xe2x80x9cC2-6 alkynyl groupxe2x80x9d represented by R5 in the specification refers to an alkynyl group having 2 to 6 carbon atoms, and examples thereof include linear or branched C2-6 alkynyl groups such as an ethynyl group, 1-propynyl group, 2-propynyl group, butynyl group, pentynyl group and hexynyl group.
Preferable examples of R5 in the specification include a hydrogen atom and a halogen atom (for example, a fluorine atom, chlorine atom, bromine atom etc.).
The partial structure: 
may be either a group represented by the formula  greater than C(R6)xe2x80x94CH2xe2x80x94 (wherein R6 is a hydrogen atom or a halogen atom) or  greater than Cxe2x95x90CHxe2x80x94, preferably a group represented by the formula  greater than C(R6)xe2x80x94CH2xe2x80x94 wherein R6 is a hydrogen atom or a halogen atom. Herein, the xe2x80x9chalogen atomxe2x80x9d represented by R6 means an atom having the same meaning as the halogen atom in the above definition, and R6 is preferably a hydrogen atom, fluorine atom, chlorine atom or bromine atom, more preferably a hydrogen atom or fluorine atom. That is, the group which can be represented by the partial structure is more preferably the formula  greater than CHxe2x80x94CH2xe2x80x94,  greater than C(F)xe2x80x94CH2xe2x80x94,  greater than C(Cl)xe2x80x94CH2xe2x80x94 or  greater than C(Br)xe2x80x94CH2xe2x80x94, further preferably the formula  greater than CHxe2x80x94CH2xe2x80x94 or  greater than C(F)xe2x80x94CH2xe2x80x94.
The xe2x80x9chalide ionxe2x80x9d represented by Xxe2x88x92 in the specification refers to a fluoride ion, chloride ion, bromide ion, iodide ion etc., preferably a chloride ion, bromide ion and iodide ion, more preferably a chloride ion and bromide ion, most preferably a chloride ion. The xe2x80x9corganic sulfonic acid ionxe2x80x9d represented by Xxe2x88x92 refers to a methanesulfonate ion, trifluoromethanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion and camphor sulfonate ion etc.
In the specification, m is 0 or an integer from 1 to 5, whereupon the partial structure: 
represents (1) the formula  greater than C(R6)xe2x80x94CH2xe2x80x94 or  greater than Cxe2x95x90CHxe2x80x94 when m is 0, (2) the formula  greater than C(R6)xe2x80x94(CH2)2xe2x80x94 or  greater than C=CHxe2x80x94(CH2)xe2x80x94 when m is 1, (3) the formula  greater than C(R6)xe2x80x94(CH2)3xe2x80x94 or  greater than Cxe2x95x90CHxe2x80x94(CH2)2xe2x80x94 when m is 2, (4) the formula  greater than C(R6)xe2x80x94(CH2)4xe2x80x94 or  greater than Cxe2x95x90CHxe2x80x94(CH2)3xe2x80x94 when m is 3, (5) the formula  greater than C(R6)xe2x80x94(CH2)5xe2x80x94 or  greater than Cxe2x95x90CHxe2x80x94(CH2)4xe2x80x94 when m is 4, and (6) the formula  greater than C(R6)xe2x80x94(CH2)6xe2x80x94 or  greater than Cxe2x95x90CHxe2x80x94(CH2)5xe2x80x94 when m is 5, respectively (in the formula, R6 has the same meaning as defined above). m is preferably 0, 2 or 4, more preferably 0 or 2.
The best mode of the acetylcholinesterase inhibitor in the present invention includes, for example, those acetylcholinesterase inhibitors comprising the following compounds. However, it goes without saying that the embodiments of the present invention are not limited to those acetylcholine esterase inhibitors comprising these compounds.
The acetylcholinesterase inhibitor comprises any one or two or more 1-benzylpyridinium salts selected from:
1-benzyl-4-(1-indanone-2-yl)methylpyridinium chloride;
1-benzyl-4-[(4-methoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(5-methoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(6-methoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(7-methoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(5,7-dimethoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(4,7-dimethoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(4,5-dimethoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(6,7-dimethoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(5,6,7-trimethoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-[(5,6-diethoxy-1-indanone)-2-yl]methylpyridinium chloride;
1-benzyl-4-(1-indanone-2-yl)methylpyridinium bromide;
1-benzyl-4-[(4-methoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(5-methoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(6-methoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(7-methoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(5,6-dimethoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(5,7-dimethoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(4,7-dimethoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(4,5-dimethoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(6,7-dimethoxy-1-indanone)-2-yl]methylpyridinium bromide;
1-benzyl-4-[(5,6,7-trimethoxy-1-indanone)-2-yl]methylpyridinium bromide; and
1-benzyl-4-[(5,6-diethoxy-1-indanone)-2-yl]methylpyridinium bromide.
The 1-benzylpyridinium salt represented by the above formula (I) as the active ingredient in the acetylcholinesterase inhibitor according to the present invention can be produced by a known method or its analogous method. Typical methods include a production method described, for example, in JP-A 11-263774 and a process for producing a benzylpyridinium salt (I) described in JP-A 8-225527.
The starting compound in production of the 1-benzylpyridinium salt (I) as the active ingredient in the acetylcholinesterase inhibitor according to the present invention may have formed a salt or a hydrate and is not particularly limited insofar as the reaction is not inhibited. Further, when Compound (I) according to the present invention is obtained in a free form, it can be converted in a usual manner into a salt which Compound (I) may form. Further, the resulting various isomers (for example, geometric isomer, optical isomer based on asymmetric carbon, stereoisomer, tautomer etc.) of Compound (I) according to the present invention can be purified and isolated by usual separating means, for example, re-crystallization, diastereomer salt method, enzyme fractionation method, and various kinds of chromatography (for example, thin layer chromatography, column chromatography, gas chromatography etc.).
The acetylcholinesterase preparation according to the present invention can be manufactured by a conventional method, and preferable preparation forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalations, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices and lotions. Ordinarily used fillers, binders, disintegrating agents, lubricants, coloring agents, flavoring agents and as necessary stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives and antioxidants can be used in pharmaceutical manufacturing, and ingredients used generally as starting materials for pharmaceutical preparations can be blended in a usual manner for manufacturing. These ingredients include e.g. (1) animal and vegetable oils such as soybean oil, tallow and synthetic glyceride; (2) hydrocarbons such as liquid paraffin, squalane and solid paraffin; (3) ester oils such as octyldodecyl myristate and isopropyl myristate; (4) higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5) silicon resin; (6) siliconoil; (7) surfactants such as polyoxyethylene fatty ester, sorbitan fatty ester, glycerin fatty ester, polyoxyethylene sorbitan fatty ester, polyoxyethylene hardened castor oil and polyoxyethylene polyoxypropylene block copolymer; (8) water-soluble polymers such as hydroethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; (9) lower alcohols such as ethanol and isopropanol; (10) polyvalent alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; (11) sugars such as glucose and sucrose; (12) inorganic powder such as silicic anhydride, aluminum magnesium silicate and aluminum silicate; and (13) pure water.
1) The fillers include e.g. lactose, corn starch, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide etc.; 2) the binders include e.g. polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, arabic gum, tragacanth, gelatin, shellac, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block polymer, meglumine, calcium citrate, dextrin, pectin etc.; 3) the disintegrating agents include e.g. starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium etc.; 4) the lubricants include e.g. magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil etc.; 5) the coloring agents include e.g. those which are approved to be added to pharmaceutical preparations; 6) the flavoring agents include cocoa powder, menthol, aromatic powder, peppermint oil, borneol, cinnamon powder etc.; and 7) the antioxidants include those which are approved to be added to pharmaceutical preparations such as ascorbic acid and xcex1-tocopherol.
1) The oral preparation is produced by mixing Compound (I) or a salt thereof with fillers and if necessary with a binder, a disintegrating agent, a lubricant, a coloring agent, flavoring agents etc.; and then forming it in a usual manner into powders, fine granules, granules, tablets, coated tablets, capsules etc. 2) The tablets and granules may be coated with a sugar or gelatin coating or if necessary with another suitable coating. 3) The liquid preparations such as syrups, injections, eye drops etc. are prepared by mixing with a pH adjuster, a solubilizer and an isotonizing agent together with, if necessary, a solubilizing aid, a stabilizer, a buffer, a suspension agent and an antioxidant, followed by forming it into the preparations in a usual manner. The liquid preparation may be formed into a freeze-dried product and the injection can be administered intravenously, subcutaneously or intramuscularly. Preferable examples of the suspension agent include methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, arabic gum, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate etc.; preferable examples of the solubilizing aid include polyoxyethylene hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate etc.; preferable examples of the stabilizer include sodium sulfite, sodium metasulfite, ether etc.: preferable examples of the preservative include methyl p-oxybenzoate, ethyl p-oxybenzoate, sorbic acid, phenol, cresol, chlorocresol etc. 4) The agent for external application can be produced in any of the conventional processes without any limit to the process thereof. The starting base material can make use of various starting materials ordinarily used in pharmaceutical preparations, non-pharmaceutical preparations, cosmetics etc.; for example, the starting base material includes animal and vegetable oils, mineral oil, ester oil, waxes, higher alcohols, fatty acids, silicon oil, surfactants, phospholipids, alcohols, polyvalent alcohols, water-soluble polymers, clay minerals, pure water etc., and if necessary, a pH adjuster, an antioxidant, a chelating agent, a preservative, a coloring agent, a perfume etc. can further be added. Further, ingredients having a differentiation-inducing action, a blood-stream promoting agent, a sterilizer, an antiinflammatory agent, a cell activator, vitamins, amino acids, a humectant and a keratin solubilizer can also be incorporated as necessary.
Although the dose of the acetylcholinesterase preparation according to the present invention is varied depending on severity of symptoms, age, sex, body weight, administration form, type of salt, chemical sensitivity and type of disease, and in the case of an adult, it is administered in a dose of generally about 30 xcexcg to 1000 mg, preferably 100 xcexcg to 500 mg and more preferably 100 xcexcg to 100 mg for oral administration, or about 1 to 3000 xcexcg/kg, preferably 3 to 10000 xcexcg/kg for injection per day in one or several portions.
The acetylcholinesterase inhibitor according to the present invention exhibits an excellent inhibitory effect on acetylcholinesterase, and is useful as an agent for treating, preventing or improving senile dementia, cerebrovascular dementia or attention deficit hyperactivity disorder. In particular, it is useful as an agent for treating, preventing or improving Alzheimer type senile dementia.